In ophthalmology, the use of a combination of an antibiotic and an anti-inflammatory drug for the treatment of inflammation associated with infection of the anterior ocular segment, especially conjunctivitis, has been found useful. For example, Leibowitz HM et al. Human Conjunctivitis. Arch Ophthalmol, 1976; 94:1752-6 report that the combination of a corticosteroid and an antibiotic is more effective than the antibiotic alone in the treatment of bacterial acute conjunctivitis.
Non-steroid anti-inflammatory drugs (NSAIDs) were introduced to ophthalmology as an alternative to corticosteroids. It is presently thought that the efficacy of available NSAIDs is comparable to that of the weaker corticosteroids. However, NSAIDs lack the adverse side effects associated with corticosteroids such as the increase in intraocular pressure and the unfavorable immune-suppressant effect that corticosteroids have with viral, fungal, tubercular and other types of infections.
In surgical treatment of the anterior segment of the eye, for example, in cataract surgery, post-operative inflammation can be reduced by the pre-operative and post-operative use of NSAIDs administered to the eye.
There is a correlation between the blepharoconjunctival microbial flora present in the pre-operative stage of cataract surgery and the infectious agents isolated from post-operative endooophthalmitis. For this reason, it is common practice to sterilize or disinfect the external eye structure, both prior to surgery and post-operatively, until there is no longer a possibility of infection in the surgical wound, by treatment with an antibiotic. A combination of antibiotics and either asteroid or a NSAID is also used for treatment of ear infections and ear injuries. This was described by Alexander J et al. A new corticosteroid-antibiotic preparation in eye and ear infections. General Practitioner Clinical Trials 1966; 176:94-96 herein incorporated by reference.
The use of a combination of asteroid and an antibiotic for treatment of eye and ear disorders in veterinary medicine is well known. The same drugs used to treat humans are also used to treat animals, since the eye and ear disorders that are common in veterinary practice have the same physiopathology as human disorders. This is described by Moore CP. Conjuntival disorders. In Current Veterinary Therapy, X Small Animal Practice. Philadelphia: WB Saunders Company, 1989, herein incorporated by reference, Brooks DE. Canine conjunctiva and nictating membrane. In Veterinary Ophthalmology. 2nd Ed. Edited by Gelatt KN. Philadelphia: Lea and Febiger, 1991, herein incorporated by reference and Macy DW. Diseases of the ear. In Textbook of Veterinary Internal Medicine. Diseases of the dog and cat. Edited by Ettinger SJ. Philadelphia: Saunders Company, 1989, herein incorporated by reference.
The use of steroidal anti-inflammatory agents with antibiotics in general and with Tobramycin in particular is well known. This has been described by Cagle et al. in their PCT application WO 89/09057, herein incorporated by reference, where Cagle uses the steroids Dexamethasone, Fluoromethalone and Fluoromethalone acetate with Tobramycin for treatment of eye infections accompanied by inflammation and by Leibowitz HM et al. 1976 as previously mentioned.
The use of a NSAID with an antibiotic, however, is not well documented, and no combination of a NSAID and an antibiotic has been marketed. Canadian Patent Application No. 2,013,188 (Fu et al.), describes an ophthalmic formulation comprising an NSAID with Tobramycin in a solution with a suitable preservative. The preferred ophthalmic formulation of Fu et al. used the NSAID ketorolac tromethamine with the antibiotic Tobramycin. The preferred ophthalmic formulation of Fu et al. comprises ketorolac tromethamine, Tobramycin, a non-ionic surface active agent, preferably Octoxymol 40, and a preservative selected from the group of quaternary ammonium compounds. Fu et al. reports that the use of non-ionic surface active agents, especially polyoxyethylene alkylphenol surfactants, avoids the unacceptable interactions between NSAID and quaternary ammonium compounds, wherein the NSAID and quaternary ammonium compound form a complex that is either insoluble or retards the absorption of the NSAID.
However, as will be described in greater detail hereinafter, when we attempted to prepare a formulation of Tobramycin and Diclofenac, as possibly suggested by Fu et al., we discovered that the formulation of Tobramycin and Diclofenac formed a precipitate which would be pharmaceutically unacceptable in a formulated product.
Hence, up until our invention, there still was a need for a pharmaceutically acceptable formulation of Tobramycin and Diclofenac for ophthalmological and otic use.